1-Methylpyrrolidine → HCID 67490977, compound

N-methylpyrrolidine (0.246 mL, 2.37 mmol) and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (306 mg, 0.79 mmol) were added to a solution of (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane (193 mg, 0.79 mmol) in acetonitrile (10.0 mL), and the mixture was heated to reflux for 10 hours. 1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (92 mg, 0.24 mmol) was added again to the reaction solution, and the mixture was further heated to reflux for 4.5 hours. The solvent was evaporated under reduced pressure, and then the residue was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The resulting oil (409 mg) was dissolved in concentrated hydrochloric acid (3.0 mL) under ice-cooling, and the solution was stirred at room temperature for 2.5 hours. The reaction solution was washed with chloroform twice, and then the aqueous layer was adjusted to pH 12 with a saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and the insoluble material was removed by filtration. Then, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by recrystallization from ethanol to give 47 mg of the title compound as a pale yellow solid.

1. temperaturethe mixture was heated
2. temperatureto reflux for 10 hours
3. temperaturethe mixture was further heated
4. temperatureto reflux for 4.5 hours
5. customThe solvent was evaporated under reduced pressure
6. extractionthe residue was extracted with a 10% citric acid solution and ethyl acetate
7. washThen, the organic layer was washed with water twice
8. dry with materialbrine, dried over anhydrous sodium sulfate
9. filtrationfiltered
10. customThereafter, the solvent was evaporated under reduced pressure
11. dissolutionThe resulting oil (409 mg) was dissolved in concentrated hydrochloric acid (3.0 mL) under ice-
12. temperaturecooling
13. washThe reaction solution was washed with chloroform twice
14. extractionfollowed by extraction with chloroform
15. dry with materialThe organic layer was dried over anhydrous sodium sulfate
16. filtrationfiltered
17. customthe solvent was evaporated under reduced pressure
18. additionChloroform was added to the residue
19. customthe insoluble material was removed by filtration
20. customThen, the filtrate was evaporated under reduced pressure
21. customthe resulting residue was purified by recrystallization from ethanol

ORD record

ord-c3377c5f4b5d442d9bc58e19cdf31e89

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618094B2